Background: Nanoparticles (NPs) for large surface area and unique physicochemical properties
have a potential to perform excellent catalytic activity in comparison to bulk materials. As part of our growing
program to design fundamental and potent methods for the synthesis of heterogeneous catalyst and organic compounds,
We characterize preparation functionalization, and application of silica nanoparticles (silica NPs)/
nanosilica sulfuric acid (NSSA) as novel heterogeneous catalyst for one-pot combinatorial synthesis sterically
congested 2-(heteroaryl)acetamide derivatives from an isocyanide, a secondary amine and heteroarylcarbaldehydes
at room temperature in excellent yields under mild conditions.
Methods: A general synthetic route to the synthesis of 2-(heteroaryl)acetamide derivatives has been developed
using silica nanoparticles/nanosilica sulfuric acid (Silica NPs / NSSA) as a reusable catalyst under solventfree
conditions. The multicomponent reactions of heteroarylcarbaldehyde, a secondary amine and isocyanide
were carried out to afford some sterically congested 2-(heteroaryl)acetamide derivatives in high yields.
Results: Silica nanoparticles/nano silica sulfuric acid (Silica NPs/NSSA) acts as excellent solid acid system to
condensation aldehyde, amine and isocyanide in high yields. It seems that the size of silica nanoparticles enhances
the catalytic activity of this solid catalyst, providing a more heterogeneous effective surface area in the
reaction media. Furthermore, nano silica sulfuric acid as an H+ source, promotes the condensation step between
a secondary amine and heteroarylcarbaldehydes to produce iminium ion intermediate and followed accelerated
the nucleophilic addition of the alkyl isocyanide to afford products. Another advantage is that the
reaction proceeds cleanly and smoothly at ambient temperature and pure product were achieved. Based on the
TLC investigations, when the three-component reaction was performed in the absence of Silica NPs/NSSA,
several by-products were observed. Furthermore, we investigated effect of electronic structure of aldehyde
derivatives on the yield of the corresponding product. In the presence of benzaldehyde, the yield of target was
very low and several by-products were achieved but when electron-poor aldehyde derivatives such as
2-pyridinecarbaldehyde, 2-thiophenecarbaldehyde and 4-pyridinecarbaldehyde were used in three-component reaction,
the yield of the product was improved. Moreover, the reusability of catalyst was investigated to verify its
activity in the multicomponent reaction. The silica NPs/NSSA catalyst could be easily separated from the reaction
medium with centrifuge at 8000 rpm for 15 min and thoroughly washed with CH2Cl2. The activity of reused
silica NPs/NSSA catalyst compared to initial activity after 5 cycles decreased gradually to about 75%.
Conclusion: In conclusion, we introduce an efficient and powerful route for the one-pot synthesis of sterically
congested 2-(heteroaryl)acetamide derivatives from simple and readily available alkyl isocyanides, secondary
amine and heteroarylcarbaldehyde in the presence of silica nps and nssa (100/10). This procedure offers significant
advantages such as ease of work-up, mild reaction conditions, high yields and cleaner reaction profiles
which makes it a useful addition to modern synthetic methodologies.